The dysregulation of the adipocyte derived hormone Adiponectin induces a complex reorganization of peripheral tissue metabolism and contributes to the intricate phenotype presented in the metabolic syndrome. Though the molecular mechanisms mediating the effects of Adiponectin remain unclear, it appears to work at least in part through activation of the AMP-Activated Protein Kinase (AMPK). The mechanisms of Adiponectin activation of AMPK are unknown. Three significant advances could result from discovering the mechanisms by which Adiponectin activates AMPK: 1) an understanding of the coordinated regulation of insulin sensitivity and cardiovascular function, 2) the deeper understanding of the mechanism (s) that allow AMPK to respond to complex stimuli that may not reflect a cellular low energy state, and 3) identification of novel therapeutic targets for treatment of the metabolic syndrome and diabetes mellitus. The proposed studies aim to identify the molecular mechanisms that allow Adiponectin to activate AMPK and provide a more complete understanding of the role of AMPK in the downstream effects of Adiponectin. These studies initially aim to distinguish between and characterize two potential mechanisms for Adiponectin activation of AMPK: AMPKKactivation or the regulated production of AMP. In addition to characterizing the mechanisms of Adiponectin activation of AMPK, this proposal seeks to identify the actions of the hormone on hepatic glucose and lipid metabolism and to determine if these actions are AMPK-dependent. Adiponectin is an adipose derived hormone that regulates peripheral tissue metabolism and its diminished levels in obese, diabetic individuals may play a role in their adverse phenotypes. These studies aim to identify the molecular mechanisms of Adiponectin action by studying its activation of the protein kinase AMPK. The characterization of this signaling pathway is important because of Adiponectin's role as an anti-diabetic, anti-inflammatory agent, whose known physiological functions read like a wish list for a metabolic syndrome drug.